Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular monomeric, heme-containing enzyme that catalyzes the first and rate limiting step of L-tryptophan (Trp) catabolism along the kynurenine pathway, leading to the production of N-formylkynurenine. 95% of Trp is metabolized through this kynurenine pathway. The kynurenine pathway (KYN) initiates the production of neuroactive and immunoregulatory metabolites, collectively known as kynurenines and provides precursors that supplement dietary niacin for the biosynthesis of NAD+ and NADP+.
By locally depleting tryptophan and increasing kynurenines, IDO1 expressed by antigen presenting cells (APCs) such as dendritic cells (plasmacystoid DCs in tumor draining lymph nodes) can greatly affect T-cell proliferation and survival and activate regulatory T cells thereby reducing proinflammatory responses. IDO1 can thus provide “immune privilege” to tissues subject to chronic inflammations such as infectious and allergic diseases, transplantation and cancer. Because such tolerogenic responses can be expected to operate in a variety of physiopathological conditions, tryptophan metabolism and kynurenine production through IDO1 might represent a crucial interface between the immune and nervous system. Expression of IDO1 is upregulated by proinflammatory cytokines and can be detected in a variety of tissues, including placenta, spleen, thymus, lung, digestive tract, and central nervous system (reviewed in Munn et al. Trends Immunol, 2013, 34, 137-43).
IDO1 has emerged as a promising molecular target of new therapeutic agents for treating cancer as well as other diseases characterized by the reduction of local Trp levels and/or to imbalances in the level of cytotoxic metabolites produced by the kynurenine pathway (reviewed in Munn et al. Trends Immunol, 2013, 34, 137-43). Indeed inhibition of IDO1 activity as a therapeutic strategy has been tested in preclinical models of many diseases, with the most widely used IDO1 inhibitor, the tryptophan analogue L-1-methyltryptophan (L-1MT). Treatment with L-1 MT, alone or in combination with other agents, attenuated disease severity in animal models of arthritis, ischemia-reperfusion injury, endotoxin shock, human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, airway inflammation, and cancer (Uyttenhove et al., Nat Med, 2003, 9, 10, 1269-1274; Holmgaard et al., J Exp Med, 2013, 210, 7, 1389-1402), among others. For cancer, IDO1 induction has been observed in vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process (Uyttenhove et al., Nat Med, 2003, 9, 10, 1269-1274; Holmgaard et al., J Exp Med, 2013, 210, 7, 1389-1402). Cervical carcinoma cells (or HeLa cells) co-cultured with peripheral blood lymphocytes (PBLs) acquire an immuno-inhibitory phenotype through up-regulation of IDO1 activity. A reduction in PBL proliferation upon treatment with interleukin-2 (IL2) was believed to result from IDO1 released by the tumor cells in response to gamma interferon (IFN)-g (γ) secretion by the PBLs. IDO1 activity in tumor cells may thus serve to impair anti-tumor responses, a process in which IFNg plays a central role. Further evidence for a tumoral immune resistance mechanism based on tryptophan degradation by IDO1 comes from the observation that most human tumors constitutively express IDO1, and that expression of IDO1 by immunogenic mouse tumor cells prevents their rejection (reviewed in Munn et al., Front Biosci, 2012, 4, 734-45; Godin-Ethier et al. Clin Cancer Res 2011, 17, 6985-6991; Johnson et al. Immunol Invest 2012, 41, 6-7, 765-797). This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO1, in the absence of noticeable toxicity (Holmgaard et al., J Exp Med, 2013, 210, 7, 1389-1402).
IDO1 expression has been demonstrated by immunohistochemistry in a wide spectrum of cancer patients. IDO1 mRNA, protein or modification of the ratio of tryptophan and kynurenine in the blood have been detected in patients with malignant melanoma, acute myelogenous leukemia, pancreatic, colorectal, prostate, cervical, brain, endometrial and ovarian cancers amongst others. In several malignancies, the presence of IDO1 is an independent predictor of a worse clinical outcome (reviewed in Munn et al., Front Biosci, 2012, 4, 734-45)
Although the potential of the IDO1 inhibitors as pharmaceutical agents has generated a significant interest, the initial inhibitors were identified by modification of Trp but not the discovery of molecules bearing novel structural skeleton. In the early 2000's, the best IDO1 inhibitors were mainly comprised of competitive Trp derivatives (like L-1-MT) and noncompetitive carbolines, which displayed affinities in the micromolar range. Since 2006, some potent nanomolar IDO1 inhibitors with novel structural skeleton have been discovered by high throughput screening, computational screening or natural product isolation and optimization of the core pharmacophores in the structures. Many of these IDO1 inhibitors possess low micromolar activities or limited pharmacokinetics. Two IDO1 inhibitors are currently being tested in phase I/II clinical trials for the treatment of relapsed or refractory solid tumors (reviewed in Dolutit et al., Expert Opin Ther Pat. 2013, 23, 1367-81).
In parallel, the importance of awakening and solidifying tumor immune surveillance is now widely accepted as an important aspect of anti-cancer therapy (Motz et al., Immunity, 2013, 39, 1, 61-73). Immunoscoring of infiltrating T cell subsets is under development as biomarker approach and will allow to determine the patients' responsiveness to treatment (Galon et al., J Transl Med, 2012, 10, 1). Hence, it is still of major interest to find new potent IDO1 inhibitors.
Therefore, there is a need for new IDO1 inhibitors with improved efficacy for cancer treatment and/or prevention.